Leptin, a hormone produced by the adipocyte, increases with obesity and may be one of the mediators responsible for the elevated cardiovascular risk associated with obesity. We and others have previously shown that complete deficiency of leptin or leptin receptors in mice is protective in several models of vascular disease. Similarly, in human studies, elevated levels of leptin have been associated with increased cardiovascular risk. Although the only relevant cellular source of leptin is the adipocyte, many different cell types express the signaling form of the leptin receptor. Deficiency of hypothalamic leptin receptors or complete deficiency of leptin leads to morbid obesity, therefore therapeutic targeting of all leptin receptors or neutralizing all circulating leptin is not feasible. It is thus important to identify relevant leptin receptor cellular pools and downstream signaling pathways responsible for the effects of leptin in vascular disease. The goal of this competing renewal is to determine the effect of different leptin receptor pools and signaling pathways on atherosclerosis using mouse models. The effect of leptin on inflammation in adipose tissue, which may be an important link between obesity and vascular disease, will also be addressed. Overall, these studies will elucidate links between adipose tissue, inflammation and vascular disease and may uncover novel therapeutic targets to reduce the vascular risk associated with obesity. PUBLIC HEALTH RELEVANCE: Obesity is epidemic in the United States and is a strong risk factor for complications of atherosclerotic vascular disease such as myocardial infarction and stroke. Leptin, a hormone produced by the adipocyte, may be one of the mediators responsible for the elevated cardiovascular risk associated with obesity. Leptin signals via leptin receptors expressed by multiple cell types, although the signaling pathways and cellular receptor pools responsible for the effects of leptin on vascular endpoints is largely unknown. The goal of this proposal is to define the leptin receptor-mediated signaling pathways and relevant leptin receptor cellular pools on atherosclerosis. In addition, the effect of leptin on adipose tissue inflammation will be addressed as this may represent a link between obesity and vascular disease. Results of these studies may identify novel targets for reducing the vascular risk associated with obesity.